1. Field of the Invention
The invention relates to processes for preparing halomethyl esters, certain alkylsulfonyloxymethyl esters and arylsulfonyloxymethyl esters of penicillanic acid 1,1-dioxide useful as intermediates in production of antibiotic 6'-acylaminopenicillanoyloxymethyl esters of penicillanic acid 1,1-dioxide; and certain novel 6-substituted and 6,6-disubstituted penicillanate esters and corresponding sulfoxides and sulfones thereof, useful as intermediates in said processes.
2. Description of the Prior Art
U.S. Pat. No. 4,234,579, issued Nov. 18, 1980, discloses penicillanic acid 1,1-dioxide and esters thereof which are readily hydrolyzable in vivo, their use as antibacterial agents and for enhancing the effectiveness of beta-lactam antibiotics against many beta-lactamase producing bacteria. Penicillanic acid, its sulfoxides and certain esters thereof, but not including the halomethyl esters or sulfonyloxymethyl esters, are disclosed as useful intermediates which, upon oxidation, form penicillanic acid 1,1-dioxide.
U.S. Pat. No. 4,244,951, issued Jan. 13, 1981, discloses novel antibacterial agents of formula (X) in which penicillanic acid 1,1-dioxide is linked to known penicillin antibiotics via a methylenedioxo group, i.e., ##STR3## where R.sup.b is the acyl group of a natural or semisynthetic penicillin. The compounds (X) are prepared, for example, by reacting a carboxylate salt of the penicillin such as the sodium, potassium or tertiary amine salt with a halomethyl ester (or related ester) of penicillanic acid 1,1-dioxide. The intermediate halomethyl esters are prepared by esterification of penicillanic acid 1,1-dioxide.
Netherlands patent application No. 8,000,775, published Aug. 15, 1980 and corresponding British patent application No. 2,044,255, also disclose compounds of formula (X) which may be prepared from intermediates of formula (I). The compounds of formula (X) and (I) are prepared in the same manner as disclosed in U.S. Pat. No. 4,244,951. These applications also disclose chloromethyl 6,6-dibromopenicillanic acid, and compounds of the formula ##STR4## where R.sub.3 is H or CH.sub.3, X.sup.1 is a leaving group such as halogen and R.sub.6 is a halogen atom. Halomethyl esters of 6-alpha-chloro- (and 6-alpha-bromo)-penicillanic acid 1,1-dioxide, prepared by esterification of the corresponding 6-alpha-halopenicillanic acid 1,1-dioxides, are also disclosed.
European patent application No. 13,617, published July 23, 1980, discloses a process for preparing beta-lactamase inhibitors of the formula (XII) and a process for their preparation from intermediates (XI) ##STR5## where R.sup.e is (inter alia) H or halogen, n is zero, 1 or 2; Y.sup.a is isocyano when R.sup.e is H, and Y.sup.a is arylselenyl when R.sup.e is chloro; R.sup.x is H or a carboxyl-blocking group, including certain tertiary amine salts and certain compatible ester-forming radicals such as benzyl, certain substituted benzyl, certain tertiary alkyl, 2,2,2-trichloroethyl, trimethylsilyl or trialkyltin esters, by treating the compound (XI) with a triaryltin hydride, dialkyltin hydride or a trialkyltin hydride and thereafter optionally carrying out one or more of the following steps:
(i) converting a sulfide (n=0), sulfoxide (n=1), or sulfone (n=2) to a different such group;
(ii) removing the carboxyl-blocking group if present;
(iii) converting the free acid into a pharmaceutical acceptable salt thereof.
U.S. Pat. No. 3,996,235 discloses 6-isocyano (C.tbd.N--) substituted penicillins, the corresponding sulfoxides, carboxylate salts and esters thereof, as well as methods for their preparation from the corresponding 6-beta-formylaminopenicillanate by reaction with phosgene in the presence of an acid acceptor. The products are isolated as mixtures of 6-alpha-isocyano- and 6-beta-isocyanopenicillianates.
Barton et al., Journal of the Chemical Society (London), Perkin I, 2657 (1980) disclose the use of tri-n-butyltin hydride in hydrogenolysis of isonitriles and isothiocyanates derived from aminoglycosides to provide the corresponding hydrocarbons.
6-Halopenicillanic acids have been disclosed by Cignarella et al., Journal of Organic Chemistry, 27, 2668 (1962) and in U.S. Pat. No. 3,206,469; hydrogenolysis of 6-halopenicillanic acids to penicillanic acid is disclosed in British patent specification No. 1,072,108.
Harrison et al., Journal of the Chemical Society (London), Perkin I, 1772 (1976) disclose: (a) the oxidation of 6,6-dibromopenicillanic acid with m-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; (b) oxidation of methyl 6,6-dibromopenicillanate with m-chloroperbenzoic acid to give a methyl 6,6-dibromopenicillanate 1,1-dioxide; (c) oxidation of methyl 6-alpha-chloropenicillanate with m-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides; and (d) oxidation of methyl 6-bromopenicillanate with m-chloroperbenzoic acid, to give a mixture of the corresponding alpha- and beta-sulfoxides.
Clayton, Journal of the Chemical Society (London) (C), 2123, (1969), discloses: (a) the preparation of 6,6-dibromo- and 6,6-diiodopenicillanic acid; (b) oxidation of 6,6-dibromopenicillanic acid with sodium periodate, to give a mixture of the corresponding sullfoxides; (c) hydrogenolysis of methyl 6,6-dibromopenicillanate to give methyl 6-alpha-bromopenicillanate; (d) hydrogenolysis of 6,6-dibromopenicillanic acid, and its methyl ester, to give penicillanic acid and its methyl ester, respectively; and (e) hydrogenolysis of a mixture of methyl 6,6-diodopenicillanate and methyl 6-alpha-iodopenicillante to give pure methyl 6-alpha-iodopenicillanate.
Belgian Pat. No. 882,028, granted Sept. 9, 1980, discloses a process for preparing penicillanic acid 1,1-dioxide and its readily hydrolyzable in vivo esters by oxidation of a 6-halopenicillanate or a 6,6-dihalopenicillanate to the corresponding 1,1-dioxide, then dehalogenation to provide the desired penicillanate 1,1-dioxide.